Review of Antidepressants & a look at the newest agent Vortioxetine Pharmacology Rounds Aug 2015 Sue Corrigan BScPharm, ACPR, PharmD

Disclosure I do NOT have any affiliation (financial or otherwise) with a pharmaceutical, medical device or communications organization I have not received any funding for speaking or advisory boards from pharmaceutical or medical device organization

Outline Pharmacology Review new agent Vortioxetine Clinical Pearls – what’s the difference between the agents Review evidence of older agents and vortioxetine

Antidepressants Selective Serotonin Reuptake Inhibitors (SSRIs) Fluoxetine, Fluvoxamine, Sertraline, Paroxetine, Citalopram, Escitalopram Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine, Desvenlafaxine, Duloxetine Norepinephrine Dopamine Reuptake Inhibitor (NDRI) Bupropion Norepinephrine and Specific Serotonin Antidepressant (NaSSA) Mirtazapine Serotonin Modulator and Stimulator Vortioxetine Tricyclic Antidepressants (TCA’s) Monoamine Oxidase Inhibitors (MAOIs)

SSRIs, SNRIs, NDRIs and TCAs are re-uptake inhibitors of 5-HT or NE aka 5-HT transporter (SERT) blockade …

Mirtazapine

Clinical Pearls – SSRIs Pros Concerns / Comments Sertraline (Zoloft®) Safe in CV disease; good efficacy data FDA analysis – reduction in SI More diarrhea High male sexual dysfunction Citalopram (Celexa®) Safe in CV disease Well tolerated QTc prolongation (40 mg max) Escitalopram (Cipralex®) Efficacy data QTc prolongation Possibly higher sexual dysfx Formulary RESTRICTED to pts on PTA Fluoxetine (Prozac®) Useful in OCD, eating d/o No weight gain, stimulating Very long half-life Fluvoxamine (Luvox®) Useful in OCD MANY MANY drug interactions Most nausea and sedation Paroxetine (Paxil®) Useful in Anxiety VERY anticholinergic, caution delrium in elderly, High discontinuation rxn, Highest sexual dysfx and Wt gain in class FDA analysis – increase in SI Overall Class Side Effects N/V/D, sexual dysfunction, SIADH, Risk of GI bleeds, sweating, dry mouth, anxiety (esp early or fast titration), tremor, headache

Consider increased Serotonin … Act on Serotonin 2 receptors (post-synaptically) Agitation, Insomnia, Anxiety, Akathisia Panic Sexual dysfunction Act on Serotonin 3 receptors (post-synaptically) Nausea, Diarrhea, GI distress Headache

Clinical Pearls - SNRIs Pros Concerns / Comments Venlafaxine (Effexor®) Lower sexual dysfunction than SSRIs Less wt gain Dual action without the TCA side effects May help neuropathic pain High incidence nausea High discontinuation rxn Desvenlafaxine (Pristiq®) Active metabolite of venlafaxine Increased cost / not covered on Plan G NOT on hosp formulary Duloxetine (Cymbalta®) May be helpful in chronic pain / neuropathy Possibly less HTN than Venlafaxine Weaker evidence of efficacy in depr Increased cost / not covered by Plan G Overall Class Side Effects N/V/D, risk of hypertension at higher doses, sexual dysfunction, SIADH, Risk of GI bleeds, sweating, anxiety (esp early or fast titration), tremor, headache, insomnia

Clinical Pearls - Others Drug Pros Concerns / Comments Bupropion (Bupropion®) Least sexual dysfunction Least wt gain (may cause wt loss) Helpful in smoking cessation Agitation, insomnia, tremor Caution with seizure hx or eating d/o Sweating Mirtazapine (Remeron®) Available as dissolvable tab Minimal GI upset or nausea Sedation (at doses 15 mg or LESS); more activating at higher doses due to NE action Weight gain Dry mouth, edema * Mirtazapine BLOCKS post-synaptic Serotonin 2 and 3 receptors – helpful for anxiety and insomnia, no GI upset * Trazodone BLOCKS Serotonin 2 receptors – helpful for insomnia

Clinical Pearls – TCA’s Serotonin and NE reuptake inhibitors ALSO block – Histamine, Muscarinic, Alpha receptors Tachycardia, hypotension Weight gain, sexual dysfunction Sedation Dry mouth, constipation, confusion/delirium risk, urinary retention, dry eyes, blurred vision Can be FATAL in overdose – cardiac toxicity, seizures Also cause sweating, tremors, SIADH, rash Helpful in OCD (esp Clomipramine) or significant anxiety, atypical depressions Desipramine and Nortriptyline often tolerated better than Amitriptyline or Imipramine

Comparative Efficacy Systematic Review for treatment of MDD (1980-2007) acute, continuation, maintenance phases; includes unpublished data Outcomes Efficacy of response, speed and onset of response, remission, maintenance of remission and QoL Acute phase treatment of MDD (N=26,349) 80 head-to-head RCTs (at least 6 wks duration), 34 placebo-controlled trials (indirect comparisons, meta-regression) Across all efficacy trials for acute phase treatment of depression 46% patients achieve remission 62% patients achieve response No reliable predictors of response Gartlehner G et al. Ann Int Med 2008;149:734-750

Results Acute Phase Treatment Results Comments Efficacy and Effectiveness ESC over CIT SER & VEN over FLX Similar rates among all agents Not clinically significant Onset of Action MIR over CIT, FLX, SER or PAR Only fair quality trials Maintaining Response or Remission No difference FLX = SER; FLV = SER; TRAZ = VEN Only 3 trials Treatment Resistant Depression STAR-D Trial: BUP = SER = VEN Another fair qual trial: VEN over CIT, FLX, SER, MIR and PAR

Assessment of Harm Adverse event profiles similar VEN: higher incidence of N/V than SSRI’s (33% vs. 22%) MIR: higher wt gain than SSRI’s PAR and VEN: highest rates of discontinuation syndrome Sexual dysfunction (overall 50% incidence) Bupropion causes significantly less PAR has highest rates among SSRI’s Insufficient evidence to draw conclusions about: Risk of Suicidality Cardiovascular events Weak evidence – VEN may increase CV risk

Cipriani A. et al. Lancet 2009;373:746-758 Sys review; Acute tx MDD; response rates, N=25928

Comments Only about 50-60% pt achieve response in acute tx trials Efficacy Escitalopram, Mirtazapine, Sertraline and Venlafaxine possibly more efficacious Tolerability Escitalopram, Sertraline, Bupropion and Citalopram possibly better tolerated Only about 50-60% pt achieve response in acute tx trials Only about 1/3 pts achieve remission If don’t respond to first SSRI tried, may respond to a different SSRI (based on STAR-D trial) Augmentation strategies if partial response …

Vortioxetine (Trintellex®) 5-HT reuptake inhibitor 5-HT 1a agonist 5-HT 1b partial agonist 5-HT 1d/3/7 antagonist In vivo non-clinical studies also demonstrated that vortioxetine enhances levels of 5-HT, NE, DA, Ach and Hist in specific areas of the brain Modulates glutamate transmission

1A: incr or decr glu; modulates memory; anxiolytic 1B: agonism antidepressant / antagonism memory impr 3: increases glu by reducing GABA; AD activity and memory impr 7: incr or decr glu; AD activity and memory impr

Serotonergic modulation of glutamate transmission Stems from findings that Ketamine’s antidepressant activity is abolished by 5-HT depletion (thus 5-HT dependent) Glutamate receptors Ionotropic: NMDA, AMPA, kainate receptors Metabotropic: Group I (mGluR1,R5) – potentiates presynaptic GLU release and NMDA currents Group II (mGluR2,R3) and Group III (mGluR4,6,7 and 8) – suppress glutamate function

Glutaminergic agents

Vortioxetine Indications and Dosing Only approved for Major Depressive Disorder NOT approved for Anxiety … multiple negative trials Black box warning – increased risk of suicidal thoughts and behavior in children, adolescents and young adults. Dosing 10 mg once daily (5 mg in elderly); may increase to 20 mg once daily as tolerated

Pharmacokinetics Absorption is not affected by food Very long half-life = 66 hrs Metabolized by CYP 2D6 and 3A4 Need dose reduction (max 10 mg/d) for 2D6-poor metabolizers Pts on 2D6 inhibitors: paroxetine, bupropion and fluoxetine Need dose increase for Pts on 2D6 inducers for more than 2 weeks (Phenytoin, Rifampin, Carbamazepine) Wash-out If changing from MAOI to Vortioxetine = 14 day washout If changing from Vortioxetine to MAOI = 21 day washout

Vortioxetine – Side Effects GI most common nausea (NNH 6), vomiting (NNH 28) and constipation (NNH 64) Dizziness Sweating Headache Dry mouth No significant weight gain Lower sexual dysfunction (20-30%) than SSRIs May cause hyponatremia rarely but can be severe Increased risk of GI bleeds when taken with NSAIDs Caution seizure disorders

Vortioxetine Systematic Review Included 11 RCTs, all placebo-controlled Trial size range: 429-779 participants 6 trials included an active comparator arm (5 – duloxetine; 1 venlafaxine) Included several doses of vortioxetine 4/11 trials considered ‘negative or failed’ by FDA Baseline MADRS score 30-34 (moderate-severe depression) 6-8 weeks duration; change in MADRS or HAM-D score; response rates and remission rates Meeker et al. Systematic Reviews 2015;4:21

Response vs. Placebo

Remission vs. Placebo Overall not significant difference from placebo in the short trial duration (6-8 wks) …

Response vs. SNRI 5 of 6 trials used duloxetine as active comparator Individual trials not powered to compare active arms Pooled comparison show data favors SNRI response rates

Remission vs. SNRI NS difference between active arms Short trial length

Considerations Interesting choice of comparator – Duloxetine Head-to-head vs. Escitalopram … Duloxetine inferior in 2/3 trials Head-to-head vs. Venlafaxine – favored VEN Were they trying to pick a “weaker” comparator??? … and yet duloxetine still had better response rates. Very “clean” patient populations – no other significant co- morbidities; no significant suicide risk; no other meds Short-term studies

Long term trial Enrolled 639 in-pts and out-pts; baseline MADRS 32 Initial 12 week open-label flexible dose – vortioxetine treatment 5 mg daily (could increase to 10 mg) from week 2-8. 76% pts achieved response; 69% achieved remission Pts who were in remission at both week 10 and 12 – 400 pts (63%) were randomized to Placebo or Vortioxetine for DB, fixed dose phase for 24 weeks Primary efficacy outcome was time to relapse of MDD with the 24 weeks of DB period J Psychopharmacol 2012;26:1408-1416

Cognitive Effects 3 of the 11 trials looked at cognitive efficacy measures (one was post-hoc analysis in trial of elderly pts) Measures Digit Symbol Substitution Test (DSST) Rey Auditory Visual Learning Test (RAVLT) Perceived Deficit Questionnaire Vortioxetine was superior to placebo for these cognitive measures Duloxetine inconsistent results vs. placebo; did not show improvement on DSST Clinically what dose this mean ?????

Cost Drug Approx Cost per Month Citalopram $20 Venlafaxine $21-42 Escitalopram $25 Desvenlafaxine $85 Sertraline $24-38 Duloxetine $74-274 Bupropion $24-47 Vortioxetine $100 Mirtazapine $14-21

Final Comments Vortioxetine has some interesting novel pharmacological properties Clinical data is very limited at this point; especially long-term use Studied in moderate-severe depression (easier to show improvements) Does not appear to be superior to (weaker) active comparators …

American Fam Physician 2015;91:5 STEPS New Drug Reviews

Final Comments … Cognitive data is very preliminary – needs to be tested more broadly to determine clinical significance in ‘real world’ trials “7-year” cautionary window with new drug releases… we’ll know more about the true serious adverse events by the year 2020 Cost – significant (2-5 x cost of our other options except duloxetine) Glutamate story in Depression … TO BE CONTINUED …

Thank-you!!!

Atypical Antipsychotic Augmentation Risperidone, Aripiprazole, Olanzapine and Quetiapine have been studied as augmenting to antidepressant therapy in pts who have not responded to monotherapy All had a small-modest effect over placebo for improvement in depression severity and remission Pooled Remission NNT 10 (8-15) … Olanzapine weakest evidence to support All caused significant side effects Sedation, Akathisia, EPS, Metabolic changes to glucose and cholesterol, Weight gain Questionable benefit on quality of life measures Would reserve for patients who have depression with psychotic features or atypical features; patients who have failed multiple trials of mono/dual antidepressant therapy; and pts who would qualify for ECT but who refuse to consent PLOS Medicine 2013;10:e1001403